The proper transport of iodide within thyroid follicular ceils is important for synthesis of thyroid hormones. Iodide transport defects may result in hypothyroidism or goiter. Pendred's syndrome is an autosomal recessive disorder defined by the triad of congenital deafness, goiter, and an impaired iodide organification. It is caused by mutations in the Pendred's syndrome (PDS) gene. Mutations in this gene also explain the molecular basis of two allelic variants of Pendred's syndrome, non-syndromic autosomal recessive deafness DFNB4 and non-syndromic familial enlarged vestibular aqueduct. The PDS gene encodes pendrin, an anion transporter belonging to the Solute Carrier Family 26A (SCL26A4). Pendrin is predominantly expressed at the apical membrane of thyrocytes, at the brush-border membrane of the renal cortical collecting duct, and in the inner ear. Although its exact roles in these tissues are not completely defined, pendrin appears to function as an iodide transporter in the thyroid and as an anion/base exchanger in the kidney. The human apical iodide transporter (hAlT) is a recently identified protein that is also expressed at the apical membrane of thyrocytes, as well as in the kidney. Despite its designated name, the function of hAlT is not established. Very preliminary functional experiments suggest that hAlT, like pendrin, may mediate iodide efflux. As of yet, it is not known whether mutations in hAlT are responsible for impaired thyroid hormonogensis or other forms of human disease. The objective of this proposal is to investigate various aspects of the function and/or regulation of pendrin and hAlT in the thyroid. The studies proposed in specific aim 1 will further characterize the iodide transport properties of pendrin. The studies proposed in specific aim 2 seek to obtain insights into the structure-function relationship of pendrin. The studies proposed in specific aim 3 will address the function of the human apical iodide transporter. Together, these studies will provide fundamental insights into the (patho)physiology of these two apical thyroid transporters and deepen our understanding of iodide transport in the thyroid.